Antitumor activity in ras-driven tumors by blocking akt and mek

Anthony W. Tolcher; Khurum Khan; Michael Ong; Udai Banerji; Vassiliki Papadimitrakopoulou; David R. Gandara; Amita Patnaik; Richard D. Baird; David Olmos; Christopher R. Garrett; Jeffrey M. Skolnik; Eric H. Rubin; Paul D. Smith; Pearl Huang; Maria Learoyd; Keith A. Shannon; Anne Morosky; Ernestina Tetteh; Ying Ming Jou; Kyriakos P. Papadopoulos; Victor Moreno; Brianne Kaiser; Timothy A. Yap; Li Yan; Johann S. De Bono

doi:10.1158/1078-0432.CCR-14-1901

Antitumor activity in ras-driven tumors by blocking akt and mek

Anthony W. Tolcher, Khurum Khan, Michael Ong, Udai Banerji, Vassiliki Papadimitrakopoulou, David R. Gandara, Amita Patnaik, Richard D. Baird, David Olmos, Christopher R. Garrett, Jeffrey M. Skolnik, Eric H. Rubin, Paul D. Smith, Pearl Huang, Maria Learoyd, Keith A. Shannon, Anne Morosky, Ernestina Tetteh, Ying Ming Jou, Kyriakos P. PapadopoulosVictor Moreno, Brianne Kaiser, Timothy A. Yap, Li Yan, Johann S. De Bono

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

Abstract

Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedulefinding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were de fi ned as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS -mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS -driven human malignancies (Trial NCT number NCT01021748).

Original language	English (US)
Pages (from-to)	739-748
Number of pages	10
Journal	Clinical Cancer Research
Volume	21
Issue number	4
DOIs	https://doi.org/10.1158/1078-0432.CCR-14-1901
State	Published - Feb 15 2015

ASJC Scopus subject areas

Oncology
Cancer Research

MD Anderson CCSG core facilities

Clinical Trials Office

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10.1158/1078-0432.CCR-14-1901

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Tolcher, A. W., Khan, K., Ong, M., Banerji, U., Papadimitrakopoulou, V., Gandara, D. R., Patnaik, A., Baird, R. D., Olmos, D., Garrett, C. R., Skolnik, J. M., Rubin, E. H., Smith, P. D., Huang, P., Learoyd, M., Shannon, K. A., Morosky, A., Tetteh, E., Jou, Y. M., ... De Bono, J. S. (2015). Antitumor activity in ras-driven tumors by blocking akt and mek. Clinical Cancer Research, 21(4), 739-748. https://doi.org/10.1158/1078-0432.CCR-14-1901

Tolcher, AW, Khan, K, Ong, M, Banerji, U, Papadimitrakopoulou, V, Gandara, DR, Patnaik, A, Baird, RD, Olmos, D, Garrett, CR, Skolnik, JM, Rubin, EH, Smith, PD, Huang, P, Learoyd, M, Shannon, KA, Morosky, A, Tetteh, E, Jou, YM, Papadopoulos, KP, Moreno, V, Kaiser, B, Yap, TA, Yan, L & De Bono, JS 2015, 'Antitumor activity in ras-driven tumors by blocking akt and mek', Clinical Cancer Research, vol. 21, no. 4, pp. 739-748. https://doi.org/10.1158/1078-0432.CCR-14-1901

@article{0098467a5c9a44dc890388240c774628,

title = "Antitumor activity in ras-driven tumors by blocking akt and mek",

abstract = "Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedulefinding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were de fi ned as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS -mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS -driven human malignancies (Trial NCT number NCT01021748).",

author = "Tolcher, {Anthony W.} and Khurum Khan and Michael Ong and Udai Banerji and Vassiliki Papadimitrakopoulou and Gandara, {David R.} and Amita Patnaik and Baird, {Richard D.} and David Olmos and Garrett, {Christopher R.} and Skolnik, {Jeffrey M.} and Rubin, {Eric H.} and Smith, {Paul D.} and Pearl Huang and Maria Learoyd and Shannon, {Keith A.} and Anne Morosky and Ernestina Tetteh and Jou, {Ying Ming} and Papadopoulos, {Kyriakos P.} and Victor Moreno and Brianne Kaiser and Yap, {Timothy A.} and Li Yan and {De Bono}, {Johann S.}",

note = "Publisher Copyright: {\textcopyright} 2014 American Association for Cancer Research.",

year = "2015",

month = feb,

day = "15",

doi = "10.1158/1078-0432.CCR-14-1901",

language = "English (US)",

volume = "21",

pages = "739--748",

journal = "Clinical Cancer Research",

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TY - JOUR

T1 - Antitumor activity in ras-driven tumors by blocking akt and mek

AU - Tolcher, Anthony W.

AU - Khan, Khurum

AU - Ong, Michael

AU - Banerji, Udai

AU - Papadimitrakopoulou, Vassiliki

AU - Gandara, David R.

AU - Patnaik, Amita

AU - Baird, Richard D.

AU - Olmos, David

AU - Garrett, Christopher R.

AU - Skolnik, Jeffrey M.

AU - Rubin, Eric H.

AU - Smith, Paul D.

AU - Huang, Pearl

AU - Learoyd, Maria

AU - Shannon, Keith A.

AU - Morosky, Anne

AU - Tetteh, Ernestina

AU - Jou, Ying Ming

AU - Papadopoulos, Kyriakos P.

AU - Moreno, Victor

AU - Kaiser, Brianne

AU - Yap, Timothy A.

AU - Yan, Li

AU - De Bono, Johann S.

PY - 2015/2/15

Y1 - 2015/2/15

N2 - Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedulefinding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were de fi ned as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS -mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS -driven human malignancies (Trial NCT number NCT01021748).

AB - Purpose: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design: We conducted a dose/schedulefinding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were de fi ned as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Results: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion: Responses in KRAS -mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS -driven human malignancies (Trial NCT number NCT01021748).

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AN - SCOPUS:84923123074

SN - 1078-0432

VL - 21

SP - 739

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JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 4

ER -

Antitumor activity in ras-driven tumors by blocking akt and mek

Abstract

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MD Anderson CCSG core facilities

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